Alkylamino- and alkylamino alkyl diarylketones

ABSTRACT

This invention relates to alkylamino and alkyl amino alkyl diarylketones of the formula ##STR1## where Ar is aryl of the formula ##STR2## where V is hydrogen, halogen, loweralkyl, loweralkoxy, CF 3 , No 2  and u is an integer of 1 to 3; X and Y are independently CH 2  --, --CH 2  -- or --CHF--; Z and W are independently --CH 2  --, --O--, --CHOH--, or --CHF--; m, n, p, q and t are integers which are independently 0 or 1; R 1  is H or loweralkyl; R 2  and R 3  are loweralkyl; and the pharmaceutically acceptable acid addition salts thereof and where applicable the geometric and optical isomers and racemic mixtures thereof. The compounds of this invention display utility as analgesic agents and as agents for alleviating various memory dysfunctions, characterized by a decreased cholinergic function, such as Alzheimer&#39;s disease.

This is a continuation of co-pending application Ser. No. 07/450,502filed on Dec. 14, 1989, abandoned.

This invention relates to alkylamino and alkyl amino alkyl diarylketonesof the formula ##STR3## where Ar is aryl of the formula ##STR4## where Vis hydrogen, halogen, loweralkyl, loweralkoxy, CF₃, and NO₂ and u is aninteger of 1 to 3; X and Y are independently CH₂ --, --CF₂ -- or--CHF--; Z and W are independently --CH₂ --, --O--, --CHOH--, or--CHF--; m, n, p, q and t are integers which are independently 0 or 1;R₁ is H or loweralkyl; R₂ and R₃ are loweralkyl; and thepharmaceutically acceptable acid addition salts thereof and whereapplicable the geometric and optical isomers and racemic mixturesthereof.

In a preferred embodiment the invention is related to compounds ofFormula I where V is elected from the group H or Cl, u is 1, t is O, andR₂, R₃ are methyl,

Throughout the specification and appended claims, a given chemicalformula or name shall encompass all geometric and stereoisomers andracemic mixtures where such isomers and mixtures exist.

In the above definitions, the term "lower" means the group it isdescribing contains from 1 to 6 carbon atoms. The term "alkyl" refers toa straight or branched chain hydrocarbon containing no unsaturation,e.g. methyl, ethyl, propyl, isopropyl, 2-butyl, neopentyl, n-hexyl,etc.; the term "alkoxy" refers to a monovalent subsituent which consistsof an alkyl group linked through an ether oxygen having its free valencebond from the ether oxygen, e.g. methoxy, ethoxy, propoxy, butoxy,pentoxy, etc.; the term "halogen" refers to a member of the halogenfamily consisting of fluorine, chlorine, bromine and iodine.

The compounds of the present invention are prepared in the followingmanner. The substituents Ar, Z, Y, X, W, R₁ through R₃ and the numbersm, n, p, q, t are as defined above unless indicated otherwise.

1. ORGANOMETALLIC METHODS

A. A halide of the formula Ar--(Z)_(m) --(Y)_(n) --Hal (II), where Halis a halogen selected from Cl, Br, and I is selected. Such halides arecommerically available or can be synthesized by conventional techniqueswell known by one of ordinary skill in the art. Compound II is reactedwith a metal, e.g. Mg, under conventional Girgnard reagent formationreaction conditions, such as in an ethereal solvent, e.g. ether,tetrahydrofuran, 1,2-dimethoxyethane, etc., at room temperature toreflux for 60 to 90 minutes to form Grignard reagent II of the formula

    Ar--(Z).sub.m --(Y).sub.n --Mg Hal                         (III).

Compound III in turn is reacted with a compound of the formula ##STR5##where R₄ is a carboxylic acid derivative, such as for example, ##STR6##where R₅ is loweralkyl; ##STR7## etc. Compound IV is well known or canbe synthesized by conventional techniques well known by one of ordinaryskill in the art. Compound III and Compound IV are reacted underconventional Grignard reaction conditions well known in the art, such asin an ethereal solvent, e.g. ether, tetrahydrofuran,1,2-dimethoxyethane, etc., at a temperature of 0 to reflux for one halfto 18 hours to form Compound I.

B. In an alternative embodiment a halide of the formula ##STR8## whereHal is a halogen selected from Cl, Br, I, is reacted with a metal, e.g.Mg, under conventional Grignard reaction conditions and then theresultant Grignard reagent is reacted with Compound VI of the formula##STR9## where R₅ is loweralkyl, to give Compound I.

C. Alternatively, where q and p are 0, Compound V is reacted with alithium reagent, e.g. tertiary-butyl lithium, n-butyl lithium, sec-butyllithium, etc. under conventional lithiation reaction conditions to forma compound having the formula ##STR10## Typically, this reaction iscarried out in an ethereal solvent, e.g. ether, tetrahydrofuran, etc.,at a temperature of -78° to 0° C. for 1 to 2 hours. Compound VII in turnis reacted with Compound VI, under conventional organometallic reactionconditions to form Compound I. Typically this reaction is carried out inan ethereal solvent, e.g. ether, tetrahydrofuran, etc., at a temperatureof -78° to 20° C. for 15 to 60 minutes.

2. BENZOIN CONDENSATION

A. An aldehyde of the formula ##STR11## is reacted with a secondaldehyde of the formula ##STR12## under conventional benzoincondensation reaction conditions to form Compound X of the invention ofthe formula ##STR13##

Typically the reaction is carried out in a manner taught by Johannes S.Buck et al., J. Chem. Soc., 52, 220 (1930).

B. Compound X may be subjected to conventional reduction by means of asuitable reducing agent, e.g. tin, zinc, etc., in a protic solvent, e.g.methanol, ethanol, etc., in the presence of a mineral acid, e.g.hydrochloric, hydrobromic, etc., at a temperature of 20° C. to refluxfor 2 to 4 hours to form Compound XI of the invention having the formula##STR14##

C. Alternatively, Compound X is reacted withdiethylaminosulfurtrifluoride in a chlorinated solvent, e.g.dichloromethane, chloroform, 1,2-dichloroethane, etc., at a temperatureof -78° to 20° C. for 24 to 48 hours to form Compound XII of theinvention having the formula ##STR15##

3. TOSYLMETHYL ISOCYANIDE SYNTHESIS

Employing the procedure of van Leusen et al., Tetrahedron Letters, No.48, pp. 4229-4232 (1977), Compound I of the invention can be obtained.Compound II and V are reacted with tosylmethyl isocyanide to formCompound I. Typically, the reaction is carried out in the presence of astrong base, e.g. sodium hydroxide, potassium hydroxide etc., initiallyfor 30 to 90 minutes at a temperature of 0° to 25° C. and then in thepresence of an acidic solvent, e.g. ethereal hydrogen chloride, etherealhydrogen bromide, etc. at a temperature of 0° to 25° C. for 5 to 30minutes to form Compound I.

4. WILLIAMSON SYNTHESIS

A. Utilizing the procedure taught in Suzuki et al., J. Pharm. Soc.Japan, 75, 54 (1955) a compound of the formula ##STR16## is reacted inthe presence of a base, e.g. potassium carbonate, sodium bicarbonate,etc., with a compound of the formula, ##STR17## where Hal is a halogenselected from Cl, Br, I, in a dipolar aprotic solvent, e.g. methyl ethylketone, dimethylformamide, acetonitrile, etc., at a temperature of 20°to 80° C. for 6 to 36 hours to form Compound XV of the invention havingthe formula, ##STR18##

B. Alternatively, a phenol of the formula Ar--OH, (XVI), in the presenceof a base, is reacted, as described above in 4A, with Compound XVII ofthe formula ##STR19## where Hal is a halogen selected from Cl, Br, andI, to form Compound XVIII of the invention having the formula ##STR20##

5. REFORMATSKII

A. A Compound of the formula ##STR21## where Hal is a halogen selectedfrom Cl, Br and I, is selected. Compound XIX is reacted in the presenceof activated zinc under typical Reformatskii reaction conditions withCompound XX having the formula ##STR22## in a solvent, e.g.,dimethylformamide, tetrahydrofuran, etc. at a temperature of 20° to 80°C. for 18 to 24 hours to form Compound XXI of the invention having theformula ##STR23## where q is 1 and W is CHOH.

B. Alternatively, a benzaldehyde of the formula ##STR24## is reactedwith a compound (XXIII) of the formula ##STR25## where Hal is as definedabove, under Reformatskii reaction conditions, as described above in 5A,to give Compound I of the invention (where m is 1 and Z is CHOH).

Alternatively, Compound XXI, where m and q are 1 and Z and W areindependently CHOH, is treated with diethylaminosulfurtifluoride asdescribed above in 2C to give Compound I where m and q are 1 and Z and Ware independently CHF.

Compounds of the present invention are useful as analgesic agents due totheir ability to alleviate pain in mammals. The activity of thecompounds is demonstrated in the 2-phenyl-1,4-benzoquinone-inducedwrithing test in mice, a standard assay for analgesic activity [Proc.Soc. Exptl. Biol. Med. 95, 729 (1957)]. The analgesic activity of someof the compounds expressed in terms of percent inhibition of writhingare given in TABLE I.

                  TABLE 1                                                         ______________________________________                                                          Dose          Inhibition                                                      (subcutaneous)                                                                              in                                                              (mg/kg of     Writhing                                      Compound          body wt.)     (%)                                           ______________________________________                                        1-(3-chlorophenyl)-3-                                                                           20            41                                            [3-(dimethylamino)-                                                           phenoxy]-2-propanone                                                          2-(3-chlorophenyl)-2,2-                                                                         20            50                                            difluoro-1-[3-dimethylamino)-                                                 phenyl]ethanone hydrochloride                                                 2,2-difluoro-1-[4-(dimethyl-                                                                    20            67                                            amino)phenyl]-2-phenylethanone                                                2-[3-(chlorophenyl)-2-fluoro-1-                                                                 20            44                                            [4-(dimethylamino)phenyl]-                                                    ethanone                                                                      2-(3-chlorophenoxy)-1-                                                                          20            69                                            [3-(dimethylamino)phenyl]-                                                    ethanone                                                                      1-(3-chlorophenyl)-3-                                                                           20            51                                            [(3-dimethylamino)phenyl]-                                                    2-propanone                                                                   3-(3-chlorophenyl)-2,2-                                                                         20            63                                            difluoro-3-hydroxy-1-                                                         [3-(dimethylamino)phenyl]-                                                    propanone hydrochloride                                                       1,1-difluoro-3-[3-                                                                              20            58                                            (dimethylamino)phenyl]-1                                                      phenyl-2-propanone                                                            propoxyphene (standard)                                                                          3.9          50                                            ______________________________________                                    

The analgesic relief of pain is achieved when the compounds of theinvention are administered to a subject requiring such treatment at aneffective oral, parenteral or intravenous dose of from 0.1 to 25 mg/kgof body weight per day. A preferred effective dose within this range isfrom 1 to 10 mg/kg of body weight per day. A particularly preferredeffective amount is about 2 mg/kg of body weight per day. It is to beunderstood, however, that for any particular subject, specific dosageregimens should be adjusted according to the individual need. It isfurther to be understood that the dosages set forth herein are examplesonly and that they do not to any extent, limit the scope of practice ofthe invention.

The compounds of the present invention can also be used for thetreatment of various memory dysfunctions characterized by decreasedcholinergic function such as Alzheimer's disease.

The utility can be ascertained by determining the ability of thesecompounds to inhibit the activity of the enzyme acetylcholinesterase andthereby increase the acetylcholine levels in the brain.

This utility can also be ascertained by determining the ability of thesecompounds to restore cholinergically deficient memory in the DarkAvoidance Assay. In this assay mice are tested for their ability toremember an unpleasant stimulus for a period of 24 hours. A mouse isplaced in a chamber that contains a dark compartment; a strongincandesent light drives it to the dark compartment, where an electricshock is administered through metal plates on the floor. The animal isremoved from the testing apparatus and tested again, 24 hours later, forthe ability to remember the electric shock.

If scopolamine, an anticholinergic that is known to cause memoryimpairment, is administered before an animal's initial exposure to thetest chamber, the animal re-enters the dark compartment shortly afterbeing placed in the test chamber 24 hours later. This effect ofscopolamine is blocked by an active test compound, resulting in agreater interval before re-entry into the dark compartment.

The results for an active compound are expressed as the percent of agroup of animals in which the effect of scopolamine is blocked, asmanifested by an increased interval between being placed in the testchamber and re-entering the dark compartment. Results of Dark AvoidanceAssay for representative compounds of this invention and a referencecompound are presented in Table 2.

                  TABLE 2                                                         ______________________________________                                        Dark Avoidance Assay                                                                                   % of animals with                                                             scopolamine induced                                                 Dose      memory deficit                                       Compound       mg/kg,s.c.                                                                              reversal                                             ______________________________________                                        2-(3-chlorophenyl)-1-                                                                        0.16      40                                                   [3-(dimethylamino)-                                                           phenyl]ethanone hydro-                                                        chloride                                                                      physostigmine  0.31      20                                                   (reference)                                                                   ______________________________________                                    

The compounds of the present invention may be administered orally, forexample, with an inert diluent or with an edible carrier. They may beenclosed in gelatin capsules or compressed into tablets. For the purposeof oral therapeutic administration, the compounds may be incorporatedwith excipients and used in the form of tablets, troches, capsules,elixirs, suspensions, syrups, wafers, chewing gums and the like. Thesepreparations should contain at least 4% alkylamino- and alkylaminoalkyldiarylketones of the invention, the active ingredient, but may be varieddepending upon the particular form and may conveniently be between 4% toabout 70% of the weight of the unit. The amount of the compound presentin such compositions is such that a suitable dosage will be obtained.Preferred compositions and preparations according to the presentinvention are prepared so that an oral dosage unit form contains between5.0-300 milligrams of the alkylamino- and alkylaminoalkyl diarylketonesof the present invention.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotes; a glidant suchas collodial silicon dioxide; and a sweetening agent such as sucrose orsaccharin or a flavoring agent such as peppermint, methyl salicylate, ororange flavoring may be added. When the dosage unit is a capsule, it maycontain, in addition to materials of the above type, a liquid carriersuch as a fatty oil. Other dosage unit forms may contain other variousmaterials which modify the physical form of the dosage unit, forexample, as coatings. Thus tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purposes of parenteral therapeutic administration, the compoundsof the present invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of thealkylamino- and alkylaminoalkyl diarylketones derivative of theinvention, but may be varied between 0.5 and about 50% of the weightthereof. The amount of active compound in such compositions is such thata suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of thealkylamino- and alkylaminoalkyl diarylketones derivative of theinvention.

The solutions or suspensions may also include the following adjuvants: asterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylene diaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

Examples of some of the compounds include:

2-(3-fluorophenyl)-1-[3-dimethylamino)phenyl]ethanone;

2-(3-iodophenyl)-1-[3-dimethylamino)phenyl]ethanone;

2-(3-trifluorophenyl)-1-[3-dimethylamino)phenyl]ethanone;

2-(3-methylphenyl)-1-[3-dimethylamino)phenyl)]ethanone;

2-(2-chlorophenyl)-1-[3-(dimethylamino)phenyl]ethanone;

2-(3,4-dichlorophenyl)-1-[3-(diethylamino)phenyl]ethanone;

2-(3-chlorophenyl)-1-[3-(N-ethyl-N-methylamino)phenyl]ehtanone;

2,2-difluoro-1-[2-(dimethylamino)phenyl]-2-phenylethanone;

2,2-difluoro-1-[4-(dimethylamino)phenyl]-2-(3-methoxyphenyl)ethanone;

2,2-difluoro-1-[4-(dimethylamino)phenyl]-2-(3-chlorophenyl)ehtanone;

2-(3-nitrophenoxy)-1-[3-dimethylamino)phenyl]ethanone;

2-(3-(trifluoromethyl)phenoxy)-1-[3-dimethylamino)phenyl]ethanone;

2-(2,3-dichlorophenoxy)-1-[3-(dimethylamino)phenyl]ethanone;

3-(3-chlorophenyl)-2,2,3-trifluoro-1-[3-(dimethylamino)phenyl]propanone;

2-(3-chlorophenoxy)-2,2-difluoro-1-[3-(dimethylamino)phenyl]ethanone.

The following examples are for illustrative purposes and are not to beconstrued as limiting the invention disclosed herein.

The temperatures are given in degrees centigrade unless indicatedotherwise.

EXAMPLE 1 2-(3-chlorophenyl)-1-[3-[(dimethylamino)methyl]phenyl]ethanonehydrochloride

A solution of 5.50 g of 3-chlorobenzyl bromide in 100 ml of dry etherwas added slowly to 0.98 g of magnesium in 150 ml of dry ether undernitrogen. The Grignard reagent was stirred at ambient temperature forone hour and then added to a solution of 2.86 g of3-[(dimethylamino)methyl]benzonitrile in 150 ml of dry ether. Theresulting slurry was stirred at room temperature overnight and thenquenched with the dropwise addition of saturated ammonium chloridesolution. This was diluted with water and the layers separated. Theaqueous phase was extracted with ethyl acetate and the combined organicextracts were dried (Na₂ SO₄), filtered, and evaporated. The residue waspurified by flash chromatography (silica gel; ethyl acetate) and thentreated with ethereal HCl until acidic to wet litmus paper. Theprecipitate was collected and recrystallized from ethanol-ether to give2.2 g of 2-(3-chlorophenyl)-1-[3-[(dimethylamino)methyl]phenyl]ethanonehydrochloride, m.p. 187°-189° C.

ANALYSIS: Calculated for C₁₇ H₁₈ ClNO.HCl: 62.97% C, 5.91% H, 4.32% N,Found: 62.92% C, 5.97% H, 4.35% N.

EXAMPLE 2 2-(3-Chlorophenyl)-1-[3-(dimethylamino)phenyl]ethanonehydrochloride

A solution of 10.0 g of 3-chlorobenzyl chloride in 100 ml of dry etherwas added slowly to 2.26 g of magnesium in 75 ml of dry ether undernitrogen. The Grignard reagent was stirred at ambient temperature forone hour and then added to a solution of 4.5 g of3-dimethylaminobenzonitrile in 150 ml of dry ether. After the addition acatalytic amount of CuBr was added and the solution stirred overnight.The reaction was quenched with 200 ml of ammonium chloride solution anddiluted with water. The layers were separated and the aqueous phaseextracted with ethyl acetate. The combined organic layers were dried(Na₂ SO₄), filtered and evaporated. The residue was purified by flashchromatography (silica gel: 8:1 hexane-ethyl acetate) and then treatedwith ethereal HCl until acidic to wet litmus paper. The precipitate wascollected and recrystallized from ethanol-ether to give 3.8 g of2-(3-chlorophenyl)1-[3-(dimethylamino)phenyl]ethanone hydrochloride,m.p. 92°-94° C.

ANALYSIS: Calculated for C₁₆ H₁₆ ClNO.HCl: 61.95% C, 5.52% H, 4.51% N,Found: 62.14% C, 5.58% H, 4.57% N.

EXAMPLE 3 1-(3-Chlorophenyl)-3-[3-(dimethylamino)phenoxy]-2-propanone

A solution of 10.0 g of 3-chlorobenzyl chloride in 75 ml of dry etherwas added slowly to 2.25 g of magnesium powder in 75 ml of dry etherunder nitrogen. The Grignard reagent was stirred at ambient temperaturefor one hour and then added to a solution of 5.47 g of3-(dimethylamino)phenoxyacetonitrile in 200 ml of dry ether stirred at0° C. The reaction was warmed to room temperature overnight and thenquenched with of NH₄ Cl solution. The mixture was diluted with of waterand the layers separated. The aqueous phase was extracted with ethylacetate and the combined organic extracts were dried (Na₂ SO₄),filtered, and evaporated. The residue was purified by flashchromatography (silica gel; 8:1 hexane-ethyl acetate) and recrystallizedfrom ethyl acetate-hexane to give 4.3 g of1-(3-chlorophenyl)-3-[3-dimethylamino)phenoxy]-2-propanone, m.p. 82°-83°C.

ANALYSIS: Calculated for C₁₇ H₁₈ ClNO₂ : 67.21% C, 5.97% H, 4.61% N,Found: 67.10% C, 5.93% H, 4.60% N.

EXAMPLE 4 2,2-Difluoro-1-[4-(dimethylamino)phenyl]-2-phenylethanone

A solution of 4.0 g of 4-bromo-N,N-dimethylaniline in 50 ml of drytetrahydrofuran at -78° C. was treated with 23.5 ml of 1.7Mtert-butyllithium in pentane under nitrogen over 5 minutes with rapidstirring. After 0.5 hour, the slurry was warmed to -30° C. and added toa solution of 4.0 g of α,α-difluorophenylacetate in 50 ml of drytetrahydrofuran at -78° C. After 1 hour at -78° C., the solution wasallowed to warm to room temperature and stirred overnight. The solutionwas poured into water and extracted with ethyl acetate. Evaporation lefta solid which was purified by flash chromatography (1:1 ethylacetate-hexane) to give a powder. Recrystallization from ethylacetate-hexane gave 1.75 g of2,2-difluoro-1-[4-(dimethylamino)phenyl]-2-phenylethanone, m.p.115°-116° C.

ANALYSIS: Calculated for C₁₆ H₁₅ F₂ NO: 69.81% C, 5.49% H, 5.09% N,Found: 69.77% C, 5.49% H, 5.12% N.

EXAMPLE 52-(3-Chlorophenyl)-2,2-difluro-1-[4-(dimethylamino)phenyl]ethanone

A solution of 4.2 g of 4-bromo-N,N-dimethylaniline in 50 ml of dry etherwas treated with 9.2 ml of a 2.5M solution of n-butyllithium in hexaneunder nitrogen and stirred at room temperature for 2 hours. Thissolution was cooled to -78° C. and added to a solution of 5.4 g of ethylα,α-difluro(3-chlorophenyl)acetate in 50 ml of dry ether at -115° C.After 2 hours the solution was syringed into water and extracted withether. Evaporation left a gummy residue which was purified by flashchromatography (silica gel, 10:1 hexane-ethyl acetate) to give 2.1 g ofa powder. Recrystallization from hexane-ethyl acetate affords 1.7 g of2-(3-chlorophenyl)-2,2-difluoro-1-[4(dimethylamino)phenyl]ethanone, m.p.104°-108° C.

ANALYSIS: Calculated for C₁₆ H₁₄ ClF₂ NO: 62.04% C, 4.56% H, 4.52% N,Found: 62.23% C, 4.56% H, 4.45% N.

EXAMPLE 62-(3-Chlorophenyl)-2,2-difluoro-1-[3-(dimethylamino)phenyl]ethanonehydrochloride

A solution of 3.0 g of 3-bromo-N,N-dimethylaniline in 60 ml of drytetrahydrofuran (THF) was cooled to -78° C. and treated with 17.6 ml ofa 1.7M solution of tert-butyllithium in pentane under nitrogen. After 1hour at -78° C., this slurry was added to a solution of 3.5 g of ethylα,α-difluoro(3-chlorophenyl)acetate in 50 ml of dry THF and stirred at-78° C. for 1.5 hours. The reaction was quenched by pouring into waterand was extracted with ethyl acetate. The combined extracts wereevaporated and the residue purified by HPLC [18:1 hexane-ethyl acetate]to give 3.7 g of a oil. This oil was treated with ethereal HCl and theprecipitate was recrystallized first from ethyl acetate and thenTHF-ether to give 1.48 g of2-(3-chlorophenyl)-2,2-(difluoro-1-[3-(dimethylamino)phenyl]ethanonehydrochloride, m.p. 104°-106° C.

ANALYSIS: Calculated for C₁₆ H₁₄ ClF₂ NO.HCl: 55.51% C, 4.37% H, 4.05%N, Found: 55.44% C, 4.48% H, 3.98% N.

EXAMPLE 7 1,1-Difluoro-3-[3-(dimethylamino)phenyl-1-phenyl-2-propanone

A solution of 12.1 g of m-dimethyltoluidine and 10.4 g of tetramethylenediamine was treated with 36 mL of a 2.5M solution of n-butyl lithium inhexane under nitrogen and stirred at 45° C. for 1.5 hours. This solutionwas added to a solution of 18.0 g of ethyl α,α-difluorophenyl) acetatein 150 mL of dry tetrahydrofuran at -78° C. After 2 hours at -78° C.,this solution was poured into saturated sodium bicarbonate solution andextracted with ethyl acetate. Evaporation left an oil which was purifiedby HPLC (7:1 hexane-dichloromethane) to give 6.3 g of an oil thatcrystallized on standing. Recrystallization from ether-pentane yielded4.2 g of 1,1-difluoro-3-[3-(dimethylamino)phenyl]-1-phenyl-2-propanone,mp 76°-77° C.

ANALYSIS: Calculated for C₁₇ H₁₇ F₂ NO: 70.57% C, 5.92% H, 4.84% N,Found: 70.39% C, 5.96% H, 4.75% N.

EXAMPLE 8 1-(3-Chlorophenyl)-3-[3-(dimethylamino)phenyl]-2-propanone

A rapidly stirred mixture of 100 mL of 40% aqueous sodium hydroxide, 1.2g of tetrabutylammonium iodide, 12.9 g of tosylmethyl isocyanide and 120mL of dichloromethane was treated with 19.5 g of solid3-(dimethylamino)benzyl bromide hydrobromide. After 30 minutes, 15 g of3-chlorobenzyl bromide was added and the mixture stirred at ambienttemperature for 2 hours then separated. The aqueous phase wasneutralized and extracted with dichloromethane. The combined extractswere evaporated and the residue purified by high performance liquidchromatography (dichloromethane) to give 5.4 g of a powder. This powderwas suspended in 25 mL of ether and 10 mL of dichloromethane and treatedwith 2 mL of concentrated HCl. This mixture was swirled for 5 minutes,neutralized, and extracted with dichloromethane. Evaporation gave an oilthat was purified by flash chromatography (dichloromethane) to give 2.3g of a powder. Recrystallization from ether-hexane gave 1.7 g of1-(3-chlorophenyl)-3-[3-(dimethylamino)phenyl]-2-propanone, mp 58°-60°C.

ANALYSIS: Calculated for C₁₇ H₁₈ ClNO: 70.95% C, 6.30% H, 4.87% N,Found: 70.80% C, 6.40% H, 4.75% N.

EXAMPLE 9 1-(3-Chlorophenyl)-2-[3-(dimethylamino)phenoxy]ethanone

A slurry of 3.0 g of 3-dimethylaminophenol, 6.05 g of milled potassiumcarbonate and 75 ml of acetone was stirred at room temperature undernitrogen for 30 minutes and then a solution of 7.66 g ofα-bromo-3-chloroacetophenone in 75 ml of acetone was added dropwise. Theslurry was stirred at room temperature for 72 hours. Filtration andevaporation gave a residue which was purified by high performance liquidchromatography (7:1 hexane-ethyl acetate). The resulting solid wasrecrystallized from ethyl acetate-hexane to give 3.0 g of1-(3-chlorophenyl)-2-[3-(dimethylamino)phenoxy]ethanone, m.p. 101°-103°C.

ANALYSIS: Calculated for C₁₆ H₁₆ ClNO₂ : 66.32% C, 5.57% H, 4.83% N,Found: 66.33% C, 5.49% H, 4.81% N.

EXAMPLE 10 1-(3-Chlorophenyl)-2-[4-(dimethylamino)phenoxy]ethanone

A slurry containing 3.5 g of 4-dimethylaminophenol hydrochloride and 6.9g of milled potassium carbonate in 100 mL of 2-butanone was treated witha solution of 7.0 g of 3-chloro-α-bromoacetophenone in 75 mL of2-butanone and the whole stirred at room temperature overnight. Thereaction mixture was quenched with of saturated sodium bicarbonatesolution and extracted with dichloromethane. The extracts were dried(MgSO₄), filtered and evaporated to an oil. This oil was purified byhigh performance liquid chromatography (7:3 hexane-ethyl acetate) togive a solid. Recrystallization from ether-hexane gave 0.90 g of1-(3-chlorophenyl)-2-[4-(dimethylamino)phenoxy]ethanone, mp 69°-70° C.

ANALYSIS: Calculated for C₁₆ H₁₆ ClNO₂ : 66.33% C, 5.57% H, 4.83% N,Found: 66.14% C, 5.51% H, 4.71% N.

EXAMPLE 11 2-(3-Chlorophenoxy)-1-[3-(dimethylamino)phenyl]ethanone

A stirred slurry containing 4.24 g of 3-chlorophenol and 6.9 g of milledpotassium carbonate in 150 mL of dry 2-butanone was treated with asolution of 8.03 g of 3-dimethylamino-α-bromoacetophenone in 60 mL ofdry 2-butanone. This mixture was stirred at 40° C. under nitrogenovernight then evaporated. This mass was taken up in dichloromethane,filtered and concentrated. The residue was purified by high performanceliquid chromatography (dichloromethane) to give an oil that crystallizedon standing. Recrystallization from ether gave 4.4 g of2-(3-chlorophenoxy)-1-[3-(dimethylamino)phenyl]ethanone, mp 70°-72° C.

ANALYSIS: Calculated for C₁₆ H₁₆ ClNO₂ : 66.32% C, 5.57% H, 4.83% N,Found: 66.18% C, 5.31% H, 4.76% N.

EXAMPLE 12 2,3'-Dichloro-2,2-difluoroacetophenone

A solution of 25 g of 3-bromochlorobenzene in 100 ml ether was added toa solution of 15.1 g of tetramethylenediamine, 52.4 ml of a 2.5Msolution of n-butyllithium in hexane and 75 ml ether at -78° C. undernitrogen. After 1 hour, a solution of 31.0 g of ethylchlorodifluoroacetate in 150 ml ether was added. After warming to roomtemperature, the reaction was poured into excess ammonium chloridesolution and extracted with ether. The extracts were dried (Na₂ SO₄) andevaporated. The residue was distilled (0.1 mm Hg) to give 14.7 g of anoil which was used directly.

1-(3-Chlorophenyl)-2,2-difluoro-3-hydroxy-3-[3-(dimethylamino)phenyl]propanone

A solution of 9.3 g of 2,3'-dichloro-2,2-difluoroacetophenone and 6.8 gof 3-dimethylaminobenzaldehyde in 50 ml of dry dimethylformamide wasstirred at 0° C. as 4.0 g of activated zinc was added in small portionsunder nitrogen. The mixture was stirred overnight with gradual warmingto room temperature. The reaction was quenched with aqueous NH₄ Clsolution and the product was extracted with ethyl acetate. The combinedorganic extracts were dried (Na₂ SO₄), filtered, and evaporated. Theresidue was purified by high performance liquid chromatography (5:1hexane-ethyl acetate) and then recrystallized from ether-hexane to give1.7 g of1-(3-chlorophenyl)-2,2-difluoro-3-hydroxy-3-[3-(dimethylamino)phenyl]propanone,m.p. 105°-106° C.

ANALYSIS: Calculated for C₁₇ H₁₆ ClF₂ NO₂ : 60.10% C, 4.75% H, 4.12% N,Found: 60.13% C, 4.88% H, 4.05% N.

EXAMPLE 133-(3-Chlorophenyl)-2,2-difluoro-3-hydroxy-1-[3-(dimethylamino)phenyl]propanonehydrochloride

A solution of 6.3 g of 3-chlorobenzaldehyde and 9.5 g of2-chloro-2,2-difluoro-3'-(dimethylamino)acetophenone in 75 ml of drydimethylformamide was stirred at 0° C. as 4.0 g of activated zinc wasadded in small portions under nitrogen. The mixture was stirredovernight with gradual warming to room temperature. The reaction wasquenched with aqueous NH₄ Cl solution and the product was extracted withethyl acetate. The combined organic extracts were dried (Na₂ SO₄),filtered, and evaporated. The residue was purified by high perforamnceliquid chromatography (5:1 hexane-ethyl acetate) and the resulting oilwas treated with ethereal HCl. The salt was collected and recrystallizedfrom ethyl acetate to give 1.9 g of3-(3-chlorophenyl)-2,2-difluoro-3-hydroxy-1-[3-(dimethylamino)phenyl]propanonehydrochloride, m.p. 140°-142° C.

ANALYSIS: Calculated for C₁₇ H₁₇ Cl₂ F₂ NO₂ : 54.27% C, 4.55% H, 3.72%N, Found: 54.23% C, 4.49% H, 3.65% N.

EXAMPLE 14 Ethyl 3-(3-chlorophenyl)-2,2,3-trifluoropropionate

A solution of 25 g of ethyl3-(3-chlorophenyl)-3-hydroxy-2,2-difluoropropionate in 140 mL CH₂ Cl₂was treated with a solution of 14 g of diethylaminosulfurtrifluoride in10 mL CH₂ Cl₂ at room temperature. After 3 hours, the mixture was pouredinto aqueous NaHCO₃, extracted with ethyl acetate, dried (Na₂ SO₄) andevaporated. The residue was distilled (0.1 mm Hg) to give 18.7 g of anoil which was used directly.

3-(3-Chlorophenyl)-2,2,3-trifluoro-1-[3-(dimethylamino)phenyl]propanonehydrochloride

A solution of n-butyllithium (25.2 ml of 2.5M in hexanes) and 7.33 g oftetramethylenediamine in 100 ml of dry ether was stirred at -78° C.under nitrogen as a solution of 12.6 g of 3-bromo-N,N-dimethylaniline in75 ml of dry ether was added dropwise. The reaction was stirred at -78°C. for 2 hours and then was added to a solution of 18.5 g of ethyl3-(3-chlorophenyl)-2,2,3-trifluoropropionate in 150 mL ether at -78° C.After stirring at -78° C. for one hour, the reaction was warmed to roomtemperature. The reaction was then quenched with aqueous NH₄ Cl solutionand basified with dilute K₂ CO₃ solution. The layers were separated andthe aqueous phase extracted with ethyl acetate. The combined organiclayers were dried (Na₂ SO₄), filtered, and evaporated. The residue waspurified by high performance liquid chromatography [12:1 hexane-ethylacetate] to give 15.1 g of an oil. This material was treated withethereal HCl and the solid was collected and recrystallized from ethylacetate to give 9.3 g of3-(3-chlorophenyl)-2,2,3-trifluoro-1-[3-(dimethylamino)phenyl]propanonehydrochloride, m.p. 138°-140° C.

ANALYSIS: Calculated for: 53.99% C, 4.26% H, 3.70% N, Found: 54.71% C,4.25% H, 3.73% N.

EXAMPLE 15 1-Chloro-1,1-difluoro-3-phenylacetone

A solution of 20 g of ethyl chlorodifluoroacetate in 150 ml ether wastreated with one equivalent of benzyl magnesium chloride in 63 ml THF at-40° C. under nitrogen. After 2 hours, the reaction was poured intoaqueous NH₄ Cl and extracted with ether. Evaporation and distillation(0.1 mm Hg) of the residue gave 24.8 g of an oil which was useddirectly.

3,3-Difluoro-4-hydroxy-4-[3-(dimethylamino)phenyl]-1-phenyl-2-butanonehydrochloride

A solution of 20 g of 1-chloro-1,1-difluoro-3-phenylacetone and 13.3 gof 3-dimethylaminobenzaldehyde in 35 ml of dry dimethylformamide wasstirred at room temperature under nitrogen as 8.7 g of as activated zincwas added in three portions. The slurry was heated to 60° C. and stirredovernight. The reaction was quenched with NH₄ Cl solution, basified withK₂ CO₃ solution, and extracted with ethyl acetate. The combined organiclayers were dried (Na₂ SO₄), filtered, and evaporated. The residue waspurified by high performance liquid chromatography (6:1 hexane-ethylacetate) to give 6.2 g of an oil. This material was treated withethereal HCl and the solid was collected and recrystallized from ethylacetate to give 4.3 g of3,3-difluoro-4-hydroxy-4-[3-(dimethylamino)phenyl]-1-phenyl-2-butanonehydrochloride, m.p. 159°-161° C.

ANALYSIS: Calculated for: 60.76% C, 5.67% H, 3.94% N, Found: 60.71% C,5.86% H, 3.91% N.

EXAMPLE 16 2-(3-Chlorophenyl)-1-[4-(dimethylamino)phenyl]ethanone

A mixture of 9.08 g, of2-(3-chlorophenyl)-2-hydroxy-1-[4-(dimethylamino)phenyl]ethanone, 3equivalents of mossy tin, a spatula tip of copper (II) sulfate, 20 ml ofconcentrated HCl, and 60 ml of 95% ethanol was stirred at reflux 3hours. The mixture was basified with potassium carbonate solution andfiltered. The cake was washed with ethyl acetate and the filtrateseparated. The aqueous phase was extracted with ethyl acetate and thecombined organic layers were dried (Na₂ SO₄), filtered, and evaporated.The residue was purified by flash chromatography (10:1 hexane-ethylacetate) and then recrystallized from ethyl acetate-hexane to give 3.8 gof 2-(3-chlorophenyl)-1-[4-(dimethylamino)phenyl]ethanone, m.p.126°-128° C.

ANALYSIS: Calculated for C₁₆ H₁₆ ClNO: 70.20% C, 5.89% H, 5.12% N,Found: 70.35% C, 5.98% H, 5.06% N.

EXAMPLE 172-(3-Chlorophenyl)-2-fluoro-1-[4-(dimethylamino)phenyl]ethanone

A solution 6.7 g diethylaminosulfur trifluoride in 20 ml of drydichloromethane was stirred at -78° C. under nitrogen as a solution of12 g of 2-(3-chlorophenyl)-2-hydroxy-1-[4-(dimethylamino)phenyl]ethanonein 200 ml of dry dichloromethane was added dropwise. The mixture waswarmed to room temperature and stirred for 72 hours. The mixture waspoured into 200 ml of ice water and the layers separated. The organiclayer was dried (Na₂ SO₄), filtered, and evaporated. The residue waspurified by flash chromatography (8:1 hexane-ethyl acetate) and thenrecrystallized from ether-hexane to give 1.1 g of2-(3-chlorophenyl)-2-fluoro-1-[4-(dimethylamino)phenyl]ethanone, mp90°-92° C.

ANALYSIS: Calculated for C₁₆ H₁₅ ClFNO: 65.87% C, 5.18% H, 4.80% N,Found: 65.88% C, 5.16% H, 4.71% N.

We claim:
 1. An alkylamino-, alkylaminoalkyl diarylketone of the formula##STR26## where Ar is aryl of the formula ##STR27## where V is hydrogen,halogen, loweralkyl, loweralkoxy, CF₃, NO₂ and u is an integer of 1 to3; X and Y are independently --CH₂, --CF₂ -- or --CHF--; Z and W areindependently --CH₂ --, --O--, --CHOH--, or --CHF--; m, n, p, q and tare integers which are independently 0 or 1; R₁ is H or loweralkyl, R₂and R₃ are loweralkyl; and the pharmaceutically acceptable acid additionsalts thereof and where applicable the geometric and optical isomers andracemic mixtures thereof provided that when Z=oxygen n=1, or whenW=oxygen p=1, or when both Z and W are simultaneously oxygen, n=p=1 orwhen W=--CHOH-- and m=n=p=t=0 and u=1 then V is neither halogen norloweralkoxy.
 2. The compound as defined in claim 1 which is2-(3-chlorophenyl)-1-[3-[(dimethylamino)methyl]phenyl]ethanone and thepharmaceutically acceptable acid addition salts thereof.
 3. The compoundas defined in claim 2 wherein said salt is the hydrochloride.
 4. Thecompound as defined in claim 1 which is2-(3-chlorophenyl)-1-[3-(dimethylamino)phenyl]ethanone and thepharmaceutically acceptable acid addition salts thereof.
 5. The compoundas defined in claim 4 wherein said salt is the hydrochloride.
 6. Thecompound as defined in claim 1 which is1-(3-chlorophenyl)-3-[3-(dimethylamino)phenoxy]-2-propanone and thepharmaceutically acceptable acid addition salts thereof.
 7. The compoundas defined in claim 1 which is2,2-difluoro-1-[4-(dimethylamino)phenyl]-2-phenylethanone and thepharmaceutically acceptable acid addition salts thereof.
 8. The compoundas defined in claim 1 which is2-(3-chlorophenyl)-2,2-difluoro-1-[4-(dimethylamino)phenyl]ethanone andthe pharmaceutically acceptable acid addition salts thereof.
 9. Thecompound as defined in claim 1 which is2-(3-chlorophenyl)-2,2-difluoro-1-[3-(dimethylamino)phenyl]ethanone andthe pharmaceutically acceptable acid addition salts thereof.
 10. Thecompound as defined in claim 9 wherein said salt is the hydrochloride.11. The compound as defined in claim 1 which is1,1-difluoro-3-[3-(dimethylamino)phenyl]-1-phenyl-2-propanone and thepharmaceutically acceptable acid addition salts thereof.
 12. Thecompound as defined in claim 1 which is1-(3-chlorophenyl)-3-[3-(dimethylamino)phenyl]-2-propanone and thepharmaceutically acceptable acid addition salts thereof.
 13. Thecompound as defined in claim 1 which is2-(3-chlorophenoxy)-1-[3-(dimethylamino)phenyl]ethanone and thepharmaceutically acceptable acid addition salts thereof.
 14. Thecompound as defined in claim 1 which is1-(3-chlorophenyl)-2,2-difluoro-3-hydroxy-3-[3-(dimethylamino)phenyl]propanoneand the pharmaceutically acceptable acid addition salts thereof.
 15. Thecompound as defined in claim 1 which is3-(3-chlorophenyl)-2,2-difluoro-3-hydroxy-1-[3-(dimethylamino)phenyl]propanoneand the pharmaceutically acceptable acid addition salts thereof.
 16. Thecompound as defined in claim 15 wherein said salt is the hydrochloride.17. The compound as defined in claim 1 which is3-(3-chlorophenyl)-2,2,3-trifluoro-1-[3-(dimethylamino)phenyl]propanoneand the pharmaceutically acceptable acid addition salts thereof.
 18. Thecompound as defined in claim 17 wherein said salt is the hydrochloride.19. The compound as defined in claim 1 which is3,3-difluoro-4-hydroxy-4-[3-(dimethylamino)phenyl]-1-phenyl-2-butanoneand the pharmaceutically acceptable acid addition salts thereof.
 20. Thecompound is defined in claim 19 wherein said salt is the hydrochloride.21. The compound as defined in claim 1 which is2-(3-chlorophenyl)-1-[4-dimethylamino)phenyl]ethanone and thepharmaceutically acceptable acid addition salts thereof.
 22. Thecompound as defined in claim 1 which is2-(3-chlorophenyl)-2-fluoro-1-[4-(dimethylamino)phenyl]ethanone and thepharmaceutically acceptable acid addition salts thereof.
 23. Apharmaceutical composition comprising a compound as defined in claim 1present in an amount effective for alleviating a memory dysfunction,characterized by decreased cholinergic function, or present in ananalgesically effective amount and a suitable carrier therefor.